281 Angiotensin converting enzyme 2 (ACE2)deficiency results in endothelial dysfunction and worsens diabetic cardiomyopathy

Abstract

Incidence of heart disease and severity of heart failure is high in diabetic, than the non-diabetic. This increased risk appears to be due to hyperglycemia stimulated cardiac angiotensin II formation, which has been implicated in increased cardiac dysfunction. Angiotensin converting enzyme 2 (ACE2) is a homolog of the ACE that breaks down Ang II to Ang 1-7, that has the capacity to counter the actions of Ang II. To better define the role of ACE2 in diabetic cardiovascular complications,we examined cardiac and vascular function by echocardiography, hemodynamics and molecular signaling in male mice with genetic ablation of ACE2 in the context of the Akita model of type 1 diabetes. Type 1 diabetic cardiomyopathy in the Akita mouse model was characterized by lipotoxicity and diastolic dysfunction with preserved systolic function. Myocardial ACE2 levels were increased in the diabetic Akita mice. ACE2 deficient mice did not exhibit any signs of cardiac dysfunction. However, superimposing ACE2 deficiency in Akita mice (model of type I diabetes) resulted in systolic dysfunction, with elevated filling pressures, with restrictive diastolic filling pattern. Hyperglycemia together with ACE2 deficiency enhanced protein kinase C-dependent activation of NADPH oxidase and generation of superoxide. Further, Akita/ACE2KO myocardium exhibited increased phosphorylation of Jak2, Stat3 and ERK1/2 signaling pathways, in addition to enhanced matrix metalloproteinase (MMP)-2 and MMP-9 activation. Endothelial-dependent vasodilation was markedly impaired in mesenteric resistance artery obtained from the ACE2/Akita double mutant mice. Loss of ACE2 induced oxidative stress and modulation of pathological signaling in combination with endothelial dysfunction underlies impaired systolic function in diabetic cardiomyopathy. Enhancing ACE2 action may prevent the cardiovascular complications associated with diabetes.